In a 1960 episode of Bonanza Rhue played the wife of her "Space Seed" co-star, Ricardo Montalban. TOS actor Anthony Caruso also appeared in that episode. After Star Trek, Rhue and Montalban reunited a third time for an episode of Montalban's Fantasy Island.

She also appeared in a number of films, including the 1959 war comedy Operation Petticoat (co-starring Robert Gist), 1961's A Majority of One (with George Takei), the 1963 comedy classic It's a Mad Mad Mad Mad World, the 1964 western He Rides Tall (with George Murdock), and 1972's Stand Up and Be Counted (with Gary Lockwood and Michael Ansara).

Sadly, Rhue was diagnosed with multiple sclerosis in 1977 and was soon confined to using a cane, then crutches, and finally a wheelchair. This is, according to Harve Bennett, what kept McGivers from appearing in Star Trek II: The Wrath of Khan. When Bennett discovered Rhue's condition, he wrote McGivers out of the film, feeling it would be unfair to recast the role. Coincidentally, Rhue's "Space Seed" co-star, Ricardo Montalban (who played Khan in the episode) was also confined to a wheelchair due to health issues. Like Rhue, Montalban continued to work despite his predicament.

Regardless of her disability, Rhue continued to perform on television, albeit in roles that did not require her to stand up or walk. During this period, she appeared in such shows as Quincy, M.E. (with Robert Ito and Garry Walberg), CHiPs (with Michael Dorn), and the aforementioned Fantasy Island. She even accepted regular roles in the soap operas Days of Our Lives and Fame, the latter of which ran from 1982 through 1987 and co-starred Eric Pierpoint, Graham Jarvis, and Dick Miller. When that series was finished, she moved on to a series called Houston Knights, but it only lasted one season (1987-1988). She went on to have a recurring role on the mystery series Murder, She Wrote, on which she made her final on-screen appearance in 1996, although her health had already forced her to retire three years earlier.

Madlyn Rhue passed away on December 16th, 2003, due to her multiple sclerosis coupled with pneumonia and heart failure. She was 68 years old. Her remains were cremated.